PROJECT SUMMARY/ABSTRACT Prostate cancer is the second most common cancer in men in the United States. The first line of treatment for men with aggressive prostate cancer is hormone therapy or androgen ablation therapy. Although initial responses are observed, unfortunately, the disease commonly recurs in its aggressive hormone therapy- resistant form also known as castration resistant prostate cancer (CRPC). Current therapies for hormone therapy resistant prostate cancer or CRPC prolong the patients? lifespan by only a few months. Thus, there is an urgent need to identify the molecular mechanisms underlying the development of CRPC in order to define new strategies to overcome aggressive prostate cancer. Trop2 is a cell surface protein that is found altered in multiple types of human cancers. Our recent studies demonstrate that Trop2 is a novel promising therapeutic target for aggressive prostate cancer due to its high expression in advanced prostate cancer and its oncogenic role in the disease. The goals of the proposed research are to: 1) Establish Trop2 activation as a driver of CRPC and assess its role in tumor maintenance. 2) Investigate the molecular mechanisms through which Trop2 contributes to the development of the aggressive disease. The completion of the proposed project will lead to defining new molecular mechanisms underlying the development of aggressive prostate cancer. The proposed project will evaluate the oncogenic role of Trop2 receptor and its activation in aggressive prostate cancer in pre-clinical models of prostate cancer creating an important translational link between the proposed research and treatment of patients with aggressive disease in the near future. Due to the high expression of Trop2 in many epithelial cancers, we believe that our findings will be applicable to a broad range of cancers.